During the past decade, and particularly in the past 5 years, the general field of cellular responses to DNA damage has entered an extraordinarily prolific and exciting period. Genes for various DNA repair modes have been systematically and comprehensively cloned from several eukaryotic systems and show extensive conservation from yeasts to Drosophila to mammals. A number of these genes are implicated in several human hereditary diseases, notably the cancer-prone disease xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TII)), and most recently in hereditary colorectal cancer. The detailed characterization of these genes and the proteins they encode offers the potential of defining the complex pathology of these diseases in detailed molecular terms and the potential of beginning to consider effective therapeutic gene replacement strategies. Some of the cloned mammalian genes are being used to generate transgenic animal models which are expected to provide indispensable experimental and analytical tools, since these most of these diseases are rare in human populations. A number of genes required for DNA repair have been shown to be transcription factors, suggesting that the pathophysiology of some of the diseases mentioned above may involve aberrant gene regulation. The precise relationships between transcription and DNA repair remain to be defined. An increasing number of repair proteins have been purified and characterized. However, the specific biochemical mechanisms of many repair processes remain to be elucidated. New insights are also emerging with respect to the many complex relationships between various DNA repair modes and the cell cycle, and their relationship to the pathogenesis of cancer in general. The goal of this proposed conference is to bring together primary investigators in the world working in overlapping aspects of DNA repair, transcription, replication, genomic stability, cell cycle regulation and carcinogenesis. The primary object of the conference is to consolidate and clarify the various rapidly emerging phenomena identified above. This will be achieved in the context of a carefully selected formal program of plenary sessions which will feature leading investigators in the field of DNA repair, as well as leading investigators in transcription, replication, mutagenesis, carcinogenesis and cell cycle regulation, whose work interfaces with cellular responses to DNA damage. These plenary sessions will review aspects of cellular responses to DNA damage in the traditional Keystone conference format. The conference will also feature daily poster sessions. Equally importantly, the conference will provide an opportunity for approximately 500 investigators from around the world, including many graduate students and post-doctoral fellows, to confer informally and exchange ideas and information over a 5 day period. A conference of this scope and magnitude with the central theme of cellular responses to DNA damage, has not been offered in the United States since 1988.